Thromboxane A2引發急性腎損傷之病生理機轉與對應策略

Thromboxane A2 synthase (TXAS) is widely expressed in kidneys and cardiovascular systems and triggers thromboxane A2 (TXA2)production. Many reports found that elevated TXA2 level activates thromboxane-prostanoid (TP) receptors leading to vasoconstriction, atherosclerosis and thrombus formation. The TXA2 concentration and TP expression in the kidney also positively correlates with the severity of renal diseases. TXA2 may induce renal tubular cells and mesangial cells via the activation of TXAS and TP subsequently leading to acute renal failure. However, the significance of TXAS-TXA2-TP signaling in the kidney diseases is not fully understood. Therefore, to explore the role of further downstream signaling of TXAS-TXA2-TP in the renal diseases and to find the countervailing strategies for reducing TXA2 induced injury are important. We hypothesize that TXA2 may evoke oxidative stress to trigger Bax translocation to mitochondria and cytochrome C release to cytosol, inhibit endothelial nitric oxide synthase (eNOS) signaling, trigger NF-kappa B-mediated inflammation, influence the interaction of Nuclear factor-erythroid-2-related factor 2 (Nrf2), inhibitory Nrf2 (Keap1) and Bcl-2,depress nuclear Nrf2 translocation and downregulate heme oxygenase-1 (HO-1) expression.TXA2-induced changes may impair renal function by the enhancement of three types of programmed cell death, like Bax/Bcl-2-apoptosis, LC3-II-autophagy and caspase-1/IL-1 beta-pyroptosis in the renal cells. We will use the gene-depleted mice of TXAS-/-TP+/+, TP-/-TXAS+/+, TXAS-/-TP-/- and transgenic HO-1 mice to verify these possibilities. In the three-year project, we will etermine the following works. 1) In acute renal failure models, we will explore the role of downstream signaling after TXAS-TXA2-TP pathway including Bcl-2, Nrf2, PGI2, and eNOS in response to intravenous TXA2 challenge, antithy1.1-induced selective mesangial cell injury and ischemia/reperfusion-induced renal tubular cell injury. 2) We will determine the protective role of single knockout TXAS or TP or double knockout TXAS and TP.